gsk-2816126 and Liver-Neoplasms

Enhancer of zeste homolog 2 (EZH2) is a histone H3 lysine 27 methyltransferase that has been shown to function as an oncogene in some cancers. Previous reports have largely focused on the ability of EZH2 to regulate cell-intrinsic tumor regulatory pathways as its mechanism-of-oncogenic action. However, the role that EZH2-mediated immune suppression plays in its oncogenic activity is not fully known. In particular, the role of natural killer (NK) cells in EZH2-driven tumor growth remains incompletely understood. Here, we demonstrate that genetic or pharmacological inhibition of EZH2 induces reexpression of the chemokine CXCL10 in hepatic tumor cells. We find that histone deacetylase 10 (HDAC10) is necessary for EZH2 recruitment to the

Topics: Animals; Benzopyrans; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Chemokine CXCL10; Chemokines; Decitabine; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Histone Deacetylases; Humans; Indazoles; Indoles; Killer Cells, Natural; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Phenols; Pyridones; Sulfones; Triazoles

Little is known about the composition and generation of plasma cell subsets in patients with hepatocellular carcinoma (HCC) and how these associate with outcomes. We investigated whether, or how, plasma cells differentiate and function in patients with HCC and mice with liver tumors.. We analyzed subset composition and distribution of plasma cells in HCC samples from 342 patients who underwent curative resection at the Cancer Center of Sun Yat-sen University in China; samples of non-tumor liver tissue were used as controls. We associated plasma cell profiles with patient outcomes. Tissue-derived leukocytes were analyzed by flow cytometry and real-time polymerase chain reaction. The ability of macrophages to regulate plasma cell differentiation was determined in ex vivo cultures of cells from human HCC tissues. C57BL/6 and BALB/c mice were given injections of Hepa1-6 cells, which formed hepatomas, or H22 cells, which formed ascitic hepatomas. Gene expression patterns were analyzed in human HCC, mouse hepatoma, and non-tumor tissues by real-time polymerase chain reaction. Mice with hepatomas were given injections of GSK126 (an inhibitor of histone H3 lysine 27 methyltransferase [EZH2]) and 5-AZA-dC (an inhibitor of DNA methyltransferases); tumor tissues were analyzed by immunofluorescence and immunohistochemistry for the presence of immune cells and cytokines.. B cells isolated from HCCs had somatic hypermutations and class-switch recombinations to the IgG phenotype that were not observed in non-tumor tissues. Increased level of plasma cells correlated with poor outcomes of patients. Activated CD4. Human HCC tissues contain B cells with class-switch recombinations to the IgG phenotype. Activated CD4

Topics: Adult; Aged; Animals; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Cell Differentiation; Cell Line, Tumor; Chemokine CCL20; Chemokine CXCL10; Decitabine; Disease Progression; DNA (Cytosine-5-)-Methyltransferase 1; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Immunoglobulin G; Indoles; Interleukin-10; Interleukin-6; Liver; Liver Neoplasms; Lymphocyte Count; Macrophages; Male; Mice; Middle Aged; Neoplasm Transplantation; Phenotype; Plasma Cells; Pyridones; Receptors, CXCR3; Receptors, Fc; Signal Transduction; Transcriptome